Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling

Abstract

Inflammatory caspase-11 senses and is activated by intracellular lipopolysaccharide (LPS) leading to pyroptosis that has critical role in defensing against bacterial infection, whereas its excess activation under pathogenic circumstances may cause various inflammatory diseases. However, there are few known drugs that can control caspase-11 activation. We report here that scutellarin, a flavonoid from Erigeron breviscapus , acted as an inhibitor for caspase-11 activation in macrophages. Scutellarin dose-dependently inhibited intracellular LPS-induced release of caspase-11p26 (indicative of caspase-11 activation) and generation of N-terminal fragment of gasdermin D (GSDMD-NT), leading to reduced pyroptosis. It also suppressed the activation of non-canonical nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as evidenced by reduced apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and decreased interleukin-1 beta (IL-1 β ) and caspase-1p10 secretion, whereas the NLRP3-specific inhibitor MCC950 only inhibited IL-1 β and caspase-1p10 release and ASC speck formation but not pyroptosis. Scutellarin also suppressed LPS-induced caspase-11 activation and pyroptosis in RAW 264.7 cells lacking ASC expression. Moreover, scutellarin treatment increased Ser/Thr phosphorylation of caspase-11 at protein kinase A (PKA)-specific sites, and its inhibitory action on caspase-11 activation was largely abrogated by PKA inhibitor H89 or by adenylyl cyclase inhibitor MDL12330A. Collectively, our data indicate that scutellarin inhibited caspase-11 activation and pyroptosis in macrophages at least partly via regulating the PKA signaling pathway.

Gasdermin D in pyroptosis

“…Subsequently, cAMP activates protein kinase A (PKA), which then phosphorylates caspase 11 to inhibit its activity for the cleavage of GsdmD 158 . A flavonoid, scutellarin, has also been suggested as a possible treatment for sepsis also believed to inhibit pyroptosis by affecting the cAMP/PKA signaling pathway 159 .…”

Samotolisib Attenuates Acute Liver Injury Through Inhibiting Caspase-11-Mediated Pyroptosis Via Regulating E3 Ubiquitin Ligase Nedd4

“…Inhibition of caspase-11 activation in the liver is considered a potential therapeutic target for the treatment of sepsis . However, little is known about the therapeutic drugs that can target and inhibit caspase-11 (Ye et al, 2021). The present study revealed that ST inhibits caspase-11 activation, thereby reducing the impact of pyroptosis in hepatocytes.…”

“…Cells were seeded in 96-well plates and primed with 1 mg/ml Pam3CSK4 in Opti-MEM for 4 h. Subsequently, the cells were treated with the different compounds for specific time periods and then transfected with 1 ug/mL LPS plus FuGENE-HD (2.5%, v/v) in Opti-MEM for 16 h (Ye et al, 2021). Lytic cell death was determined using a lactate dehydrogenase (LDH) activity detection kit.…”

Prostaglandin E2 Receptor 4 (EP4) Affects Trophoblast Functions via Activating the cAMP-PKA-pCREB Signaling Pathway at the Maternal-Fetal Interface in Unexplained Recurrent Miscarriage

“…Consistent with these data, previous studies reported that EP4 receptor blockade hindered proliferation and induced apoptosis in cervical cancer cells via the EP4-PKA-CREB pathway. Moreover, reduced PKA induced apoptosis through Bcl-2/Bax-induced apoptosis [23] and activation of the caspase-8/9/11 pathway and pyroptosis [24,25]. The PKA inhibitor blocked PGE2 through EP2-and EP4-induced apoptosis, indicating that the PKA pathway is mainly responsible for PGE2-mediated inhibition of apoptosis [26].…”